tbuckley/cabot-search huggingface dataset:
PB2029: MULTIPLE MYELOMA AND SPINAL CORD COMPRESSION: THE EXPERIENCE OF THE HEMATOLOGY DEPARTMENT OF SFAX
Authors: F. Kallel, N. Siala, K. Mezghani, M. Charfi, L. Ghorbel, H. Ben Salah, Y. Fakhfekh, O. Kassar, L. Khelifa, S. Hadiji, I. Frikha, I. Ben Amor, J. Daoued, M. Medhaffar, M. Elloumi
Journal: HemaSphere (2022)

Background: Spinal cord compression (SCC) is the most serious complication in Multiple myeloma (MM). An emergency that must be diagnosed and treated promptly to preserve neurological functions and save the patient’s live. Aims: We studied the clinical, biological, and radiological features of patients with MM from southern Tunisia complicated by SCC and the different modalities of treatment. Methods: It is a retrospective study over 18 years (2003-2020) which included young patients (pts) (<65years old) with MM presented SCC and treated at the hematology department of Hedi Chaker Hospital Sfax, Tunisia. Here we are interested in studying the characteristics (clinical, biological, and radiological) of affected pts, the various revealing symptoms of SCC, the possible therapeutic modalities and the outcome of patients. Results: Among 173 young pts followed with MM, 18 had SCC (10%) which was inaugural in 5 pts (27% of cases). The average age was 53 years (36- 63 years) and the sex ratio M/F= 10/8. The MM immunoglobulin type was IgG in 6 cases, IgA in 7 cases, Ig D in 1 cases and light chains in 4 cases. Symptoms of SCC included pain, motor defects, sensory deficits and bowel and bladder dysfunction in respectively 72, 11,100 and 2% of cases. While in 2 cases the SCC was asymptomatic (11%). The spinal MRI showed a cervical compression in 2 cases (11%), a dorsal compression in 8 cases (44.5%) and lumbar compression in 8 cases (44.5%). In 17 cases, lesions were first treated by radiotherapy (which did not produce regression of the compression). Decompressive laminectomy was carried out one time. All patients underwent high doses of corticosteroids. Pts were subsequently treated by different regimens of systemic therapy (DT in 12 cases, MPT in 3 cases and VTD in 3 cases). In 17 cases a definite and steady regression of the neurological symptoms was achieved. Median overall survival was 34 months after identification of SCC. At the date of last news, around 66% of the pts were dead. Summary/Conclusion: The frequency of different localizations of compression in our studies are comparable to the literature, however, the SCC rate in our series is higher than those described in the other series in literature (10% vs 5%) the same for the rate of different symptoms at diagnosis (in literature more of asymptomatic form) which could be explained by the delay in the diagnosis of MM and by the neglect of minimal symptoms by patients and their consultation only after the installation of deficient signs.
Abstract SY39-03: Lung cancer evolution and its prognostic impact
Authors: Mariam Jamal-Hanjani
Journal: Cancer Research (2022)

Abstract Lung cancer is the leading cause of cancer-associated mortality worldwide, and genomic intratumour heterogeneity as a result of cancer evolution has been linked to therapeutic resistance and poor outcomes. TRACERx is a prospective longitudinal cancer evolution programme which aims to investigate the relationship between intratumour heterogeneity and clinical outcomes, and to map the evolutionary pathways adopted in lung cancer from early to late stage disease. Here we present our findings from mutational, copy number and mutational signature analyses in over 420 tumours, and provide insights into the shared patterns of tumour evolution and their impact on prognosis. We demonstrate a significant association between somatic copy number alteration (SCNA) intratumour heterogeneity, defined as the percentage of subclonal SCNAs as previously reported, and poor outcomes. Furthermore, we find that subclonal genome doubling, a driver of SCNA intratumour heterogeneity, is associated with poor outcome independent of clinical variables, such as tumour stage. Citation Format: Mariam Jamal-Hanjani. Lung cancer evolution and its prognostic impact [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY39-03.
Gasdermin D–mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma
Authors: Ryota Yamagishi, Fumitaka Kamachi, Masaru Nakamura, Shota Yamazaki, Tomonori Kamiya, Masaki Takasugi, Yi Cheng, Yoshiki Nonaka, Yoshimi Yukawa-Muto, Le Thi Thanh Thuy, Yohsuke Harada, Tatsuya Arai, Tze Mun Loo, Shin Yoshimoto, Tatsuya Ando, Masahiro Nakajima, Hayao Taguchi, Takamasa Ishikawa, Hisaya Akiba, Sachiko Miyake, Masato Kubo, Yoichiro Iwakura, Shinji Fukuda, Wei-Yu Chen, Norifumi Kawada, Alexander Rudensky, Susumu Nakae, Eiji Hara, Naoko Ohtani
Journal: Science Immunology (2022)

Long-term senescent cells exhibit a secretome termed the senescence-associated secretory phenotype (SASP). Although the mechanisms of SASP factor induction have been intensively studied, the release mechanism and how SASP factors influence tumorigenesis in the biological context remain unclear. In this study, using a mouse model of obesity-induced hepatocellular carcinoma (HCC), we identified the release mechanism of SASP factors, which include interleukin-1β (IL-1β)- and IL-1β-dependent IL-33, from senescent hepatic stellate cells (HSCs) via gasdermin D (GSDMD) amino-terminal-mediated pore. We found that IL-33 was highly induced in senescent HSCs in an IL-1β-dependent manner in the tumor microenvironment. The release of both IL-33 and IL-1β was triggered by lipoteichoic acid (LTA), a cell wall component of gut microbiota that was transferred and accumulated in the liver tissue of high-fat diet-fed mice, and the release of these factors was mediated through cell membrane pores formed by the GSDMD amino terminus, which was cleaved by LTA-induced caspase-11. We demonstrated that IL-33 release from HSCs promoted HCC development via the activation of ST2-positive Treg cells in the liver tumor microenvironment. The accumulation of GSDMD amino terminus was also detected in HSCs from human NASH-associated HCC patients, suggesting that similar mechanism could be involved in a certain type of human HCC. These results uncover a release mechanism for SASP factors from sensitized senescent HSCs in the tumor microenvironment, thereby facilitating obesity-associated HCC progression. Furthermore, our findings highlight the therapeutic potential of inhibitors of GSDMD-mediated pore formation for HCC treatment.
PB2203: AGEING OF LONG-TERM ALLOGENEIC HEMATOPOIETIC CELLS RECIPIENTS COMPARED TO THEIR DONORS
Authors: M. Czarnogórski, J. Sakowska, M. Maziewski, M. Zieliński, J. M. Witkowski, A. Piekarska, I. Obuchowski, M. Młyński, P. Trzonkowski, M. Dutka, A. Sadowska-Klasa, E. Zarzycka, M. Bieniaszewska, A. Hellmann, J. M. Zaucha
Journal: HemaSphere (2022)

Background: Ageing is a complex phenomenon that leads to decreased proliferative activity, gradual loss of function of the cells, and cellular senescence. Specifically, ageing of the immune system exacerbates individual’s immune response, both humoral and cellular but increases the frequency of infections. Aims: We hypothesized that a physiological aging occurs in recipients of allogeneic hematopoietic cells transplant (allo-HCT) at a faster rate when compared to their respective donors since the small number of donor transplanted cells undergo immense proliferative stress restoring the whole recipient’s hematopoiesis. To verify our hypothesis we compared molecular characterizations of ageing between recipients and donors of allo-HCT including telomeric length, proinflammatory cytokines concentration and immunophenotypic changes in main lymphocyte subsets – CD4+, CD8+, CD19+ and CD56+. Methods: Telomeric length was measured by qPCR technique and proinflammatory cytokines concentrations as well as immunophenotype were assessed by flow cytometry. Results: Median telomeric length (TL) of CD8+ lymphocytes was significantly longer in donors of 2,1kb compared to recipients 1,7kb (p = 0,02). Similar trends were observed for CD4+ and CD19+ although the results have not reached statistical significance. We have also found differences however not significant in the immunophenotype between recipients and donors in the subpopulations of CD4+ (Naïve and Effector Memory), CD8+ Eomes+ and B-lymphocytes (B1 and B2) which resembled physiological ageing-associated quantitative changes. When grouped according to imfection status, there were differences between recipients in the TNF- and Il-4 concentrations. They were higher in the recipients with lower infection risk status p=0,05 and p=0,003 respectively. Lower infection risk recipients had also a significantly greater percentage of NK cells (22,3%) than high-risk patients (9,3%) p=0,04. Summary/Conclusion: The strong difference between recipients and donors in CD8+ population may result from faster reconstitution of CD8+ lymphocytes population in a respective recipient compared to CD4+ population after allo-HCT. Quantitative changes in immunophenotype of the recipients in some lymphocyte subsets are similar to those found in the elderly, whereas proinflammatory cytokines concentrations differ only among recipients grouped according to infection risk status which seems to resemble “inflammaging”. Lower infection risk recipients also seem to have increased innate immune response. The results of our study imply that long-term allo-HCT recipients differ from their respective donors. Those molecular differences are similar to those found in physiological ageing process.
PB2329: ACQUIRED HEMOPHILIA-POTENTIALLY FATAL IF NOT TREATED PROMPTLY
Authors: S. Stankovikj, S. Stojanovska, N. Ridova, T. Ristevska, M. Cvetanoski
Journal: HemaSphere (2022)

Background: A rare but potentially life-threatening hemorrhage can occur as a result of development of autoantibodies against coagulation factors. Generally the autoantibodies are directed against factor VIII, so it`s a question of acquired hemiphilia A. Aims: To present a patient with acquired hemiphilia A and delayed diagnosis. Methods: We present a 66-year old male with a clinical presentation of a huge hematoma in his left leg and right chest. Both his medical and family history were negative for clotting disorder at any point before. The hematoma in his leg occured two months earlier and it was treated as a muscle rupture. Results: On the day of admitance to the hospital the blood tests revealed hemoglobin level 76g/L, WBC 12x10(9)/L and platelet count 693x10(9)/L. Liver and renal functional tests were in normal range as well as the glucose level. Screening hemostasis revealed prothrombin and thrombin time in normal range but signficantly prolonged APTT (activated partial thromboplastine time) 59sec (normal range 26-34). The d-dimers were 3393microg/L. Factor VIII level was 0.7% and the Bethesda assay confirmed inhibitor titer of 10.2 BU. The bleeding was treated with a by-passing agent rFVIIa (NovoSeven). Immunosuppressive treatment was started with Cyclophosphamide 100mg and Prednisone 100mg daily. On the 8-th day of hospitalisation rFVIIa was stopped as factor VIII level increased to 6.2% and the inhibitors dropped to 2 and 1.1BU subsequently. However, the next day a new hemorrhage appeared in both legs and in left arm with a drop in hemoglobin level and development of a hemorrhagic shock. It was a life-threatening condition and the patient was promptly treated with packed red cell transfusions and additional supportive therapy. A new treatment with rFVIIa was started. Patient`s clinical condition was improving slowly and he was discharged from the hospital on the 25-th day of hospitalisation with an ongoing treatment with Cyclophosphamide and Prednisone with tapered doses. Summary/Conclusion: This case report illustrates a case with acquired hemophilia A with delayed diagnosis and development of a life-threatening condition where the treatment was prolonged and the outcome uncertain. Whenever we have a patient with unexpected massive bleeding, without history of a bleeding disorder and prolonged APTT, we should consider acquired hemophilia and start treatment promptly.
P1613: SINGLE-CELL ANALYSIS FOLLOWING SARS-COV-2 MRNA VACCINE IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION RECIPIENTS
Authors: E. Tranter, B. Obermayer-Wasserscheid, M.-L. Hütter-Krönke, C. Junkuhn, I.-W. Blau, G. L. Vuong, L. Bullinger, I.-K. Na
Journal: HemaSphere (2022)

Background: Allogeneic stem cell transplantation (alloHSCT) recipients are at particularly high risk to suffer from a severe course of disease when infected with SARS-CoV-2. It has been shown that cellular and humoral responses to available vaccines are significantly impaired in this vulnerable patient cohort. However, detailed data on the adaptive immune response is still lacking. Aims: In the current study, the evolution of the adaptive immune response against SARS-CoV-2 mRNA vaccine BNT162b2 in patients after alloHSCT was longitudinally characterized. Methods: We used single-cell RNA sequencing (scRNAseq) to integrate transcriptomic information and clone identification of about 75,880 single cells from 3 AML patients who underwent alloHSCT 188 days (± 16) prior immunization with mRNA COVID-19 vaccine BNT162b2. Blood from before, after the first and after the second vaccine was collected and analyzed. Further, serological vaccine responses were assessed. Results: T cell compartment of alloHSCT recipients shows a strong distortion towards CD8+ T cells, indicating an incomplete immune cell reconstitution in the investigated patients. Upon first vaccination, newly appearing CD8+ clones can be detected in all patients. These newly appearing CD8+ clones can be traced until after the second vaccination, possibly signifying an evolving SARS-CoV-2 specific response. Differential gene expression analysis of vaccine-induced CD8+ clones revealed an enrichment in genes related to T cell activation, particularly detectable after the second vaccination. Although CD4+ T cells showed an increase in relative abundance, gene expression analysis of CD4+ clones appearing after vaccination did not show significant alteration in gene expression. The B cell compartment was diminished in all alloHSCT recipients. However, two of the three patients did achieve a protective serological titer of anti-IgG-Spike antibodies. Image:Summary/Conclusion: In this study, we show a traceable, clonal expansion of CD8+ T cells in alloHSCT recipients after vaccination with BNT162b2, signifying an antigen specific T cell response. Only after the second dose, vaccine-induced CD8+ clonotypes show an enrichment of T-cell activation related genes, emphasizing the relevance of repeated vaccination. This data sheds light on the evolution of adaptive immune response of alloHSCT patients towards SARS-CoV-2 mRNA vaccine at a single cell level, giving crucial insights beyond serological assessment and in vitro T cell activity analysis.
PB1972: PAEONIFLORIN ALLEVIATES BIPN BY REDUCING IL6 LEVELS AND MODULATING PARKIN-MEDIATED MITOPHAGY
Authors: R. Sun, Q. Sun, F. Zhang, X. Cui
Journal: HemaSphere (2022)

Background: Multiple myeloma (MM)is a common hematological malignant tumor disease. Recent years, the emergence of the proteasome inhibitor bortezomib (BTZ) has greatly improved the remission rate and survival rate of patients with MM. However，BTZ neurotoxicity limits the clinical dosage and continuity of medication, and seriously affects the application and efficacy of BTZ. Paeoniflorin (PF) has proven to have a wide range of anti-inflammatory, painful and immunomodulatory effects. It is reported that paeoniflorin has great potential in neuroprotection, which can reduce neuronal damage by reducing the secretion of IL6 and other inflammasomes. Unfortunately, the research on the improvement of paeoniflorin on Bortezomib-induced peripheral neuropathy (BIPN) is still relatively rare. Therefore, we conducted experiments to explore the therapeutic effect and mechanism of paeoniflorin on Bortezomib-induced peripheral neuropathy to explore its potential as a novel clinical treatment for BIPN. Aims: To explore the therapeutic effect of paeoniflorin on BIPN and explore its possible mechanism. Methods: The mechanism of paeoniflorin intervention in peripheral neuropathy was predicted by bioinformatics analysis. The level of IL-6 in plasma of MM patients was detected and the relationship between IL-6 level and BIPN grade was analyzed. BIPN cell models were constructed to evaluate cell mitochondrial function by cell viability, mitochondrial quality and Mito Tracker Green. Mice were given intraperitoneal injection of BTZ (1 mg/kg on days 1, 4, 8 and 11) to establish a BIPN model. The nerve injury of BIPN mice was observed by measuring ethology, motor nerve conduction velocity, HE staining, electron microscope and ROS level. Western blot was used to detect the expression of autophagy related indexes. Results: 1. The prediction of bioinformatics suggested that paeoniflorin might improve PN by intervening in inflammation levels（IL-6) and mitochondrial autophagy. (Figure 1 A-B) 2. IL-6 levels in MM patients were positively correlated with PN levels. (Figure1 C) 3. Compared with the control group, paeoniflorin could significantly improve cell viability and mitophagy level in BIPN cell model, and improved the damage to mitochondria. (Figure1 D-E) 4. Paeoniflorin could effectively improve the behavior of nerve injury in BIPN mice, improve the sciatic nerve damage in mice, and increase the expression of LC3 Ⅱ/I, beclin1 and Parkin proteins related to autophagy in the sciatic nerve of mice. (Figure1 H-I) Image:Summary/Conclusion: Paeoniflorin could significantly reduce peripheral neuropathy caused by bortezomib, which might be achieved by reducing IL6 levels to regulate PARKIN-mediated mitochondrial autophagy and mitochondrial damage.
PB1970: AS2O3 INDUCE IMMUNOGENIC CELL DEATH IN MULTIPLE MYELOMA VIA NLRP3/CASPASE SIGNALING PATHWAY
Authors: Y. Si, L. Yu, X. Yin, R. Xu, Z. Li, S. Cui
Journal: HemaSphere (2022)

Background: Multiple myeloma (MM) is a common plasma cell malignant disease, the clonal evolution of myeloma cells and the immune escape caused by it are an important mechanism of refractory drug resistance. Aims: To explored the relationship between NLRP3 / Caspase signaling pathway and immunogenic cell death (ICD) in the intervention of As2O3 on MM cell (a human myeloma-derived KM3 cell line), and explained the inhibitory effect of As2O3 on the proliferation of myeloma cells. Methods: The inhibitory and apoptotic effect of As2O3 on human MM cells was monitored by a CCK-8 method. Meanwhile, the effects of different concentrations of As2O3 on MM cell apoptosis were detected was further determined by flow cytometry. Moreover, the expression of BCL-2, BAX, PARP, HSP70/90, MHC-I, and NLRP3 at mRNA was determined by using quantitative PCR (Q-PCR). The effects of different concentrations of As2O3 on the expression of apoptosis related proteins Bcl-2, Bax, Caspas-3 and PARP were detected by ELISA. Moreover, the expression of ICD related HSP70/90 and MHC-I proteins, as well as the expression of NLRP3 and caspase-1 proteins were explored. Results: The results indicated that As2O3 could significantly inhibit human MM cell proliferation and cell death in a time- and dose-dependent manner in vitro. Meanwhile, the results also showed that As2O3 could effectively increase the expression of Bax, PARP, HSP70/90, MHC-I, and NLRP3 mRNA levels, and decrease the Bcl-2 mRNA level in human MM cells. Moreover, As2O3 could also significantly elevate the expression of NLRP3, caspase-1 proteins and ICD related proteins, leading to increase the expression of apoptosis related proteins Bax, Caspas-3, PARP. Summary/Conclusion: As2O3 can significantly induce human MM cell death in a time- and dose-dependent manner in vitro, and activate NLRP3 / caspase signaling pathway in human MM cells. As2O3 can also increase the expression level of ICD related molecules and apoptosis related molecules Bax, Caspas-3, PARP, and initiate MM cell apoptosis, indicating that As2O3 induce immunogenic cell death in multiple myeloma via NLRP3/Caspase signaling pathway. Overall, As2O3 may be a potential agent in treating human multiple myeloma in clinical practice.
PB2242: MANAGEMENT OF AUTOIMMUNE HEMOLYTIC ANEMIA.RETROSPECTIVE STUDY OF A SINGLE CENTER
Authors: I. Hortensia-Marioara, I. Ionita, I. Claudiu, D. Calamar Popovici, M. Ionita, D. Oros
Journal: HemaSphere (2022)

Background: Autoimmune hemolytic anemia (AIHA) is characterized by the production of autoantibodies to red blood cell surface antigens with destruction of red blood cells by complement and reticuloendothelial system; usually idiophatic, it is also associated with infection, lymphoproliferative disorders, autoimmune diseases, and some drugs. Aims: To evaluate in this study the clinical, biological and therapeutic aspects of AIHA. Methods: We presented this retrospective study about 110 cases of AIHA observed in the our hematology clinic, over a period of 10 years (I 2009- I 2020). We present the clinical aspects of AIHA and evaluate the management of AIHA. Results: There were 43 men and 69 women with a mean age of 47 years [19-82]. Regarding the medical history, 10 patients were with hipertension of whom 3 were receiving Methyldopa, 15 patients were diabetic, 11 had thyroid dysfunction and 20 had a history of autoimmune disease. The clinical aspects of discovery were an anemic syndrome in 83 of patients, mainly due to paleness and asthenia. Physical examination revealed icterus in 85 causes, splenomegaly in 51 causes, hepatomegaly in 17 cases, lymph node in 14 cases and fever in 31 cases. The blood tests reveald that anemia was normocytic in 43 cases and macrocytic in 64 cases. There were biological signs of hemolysis hyperbilirubinemia in 70 patients, high LDH rate in 79 patients. Direct Coombs test was positive for IgG in 77 cases, C3 in 14 cases, IgG+C3 in 19 cases. AIHA was idiophatic in 58 cases and secondary to lymphoproliferative desorders in 4 cases, autoimmune disorders in 25 cases,3 cases were secondary to Methyldopa. The therapeutic consisted of transfusion in 61 cases and, the patients underwent a corticosteroid treatment in addition to folic acid theraphy in 74 cases and etiological treatment in the non idiopathic cases. The patients that were resistant or relapse therapy were treated by splenectomy, immunosupresive drugs (azathioprine, cyclophosphamide) and anti CD20 monoclonala antibody Immunosuppressive therapy was prescribed in 24 patients, anti-CD20 monoclonal antibody were prescribed in 10 patients, the splenectomy was permormed in 25 patients and intravenous immunoglobulins in 15 patients. Summary/Conclusion: Glucocorticoids and/or intravenous immunoglobulins are the mainstay of the treatment in the majority of patients with warm AIHA. When these treatments fail, patients often require cytotoxic drugs or splenectomy.